Gene therapy still needs to overcome some major hurdles to truly fulfil its promise

In 1953, Watson and Crick published their seminal paper describing the discovery of the double helix structure of DNA. This discovery allowed scientists to understand how DNA, the building blocks of genes, enabled all life forms to pass on their anatomical and physiological traits from one generation to another. It also means that when errors occur during the replications of DNA, the mutated genes are passed on as well, potentially resulting in devastating genetic disorders. Before scientists could find a cure for these conditions, they had to first map out the entire human genome. In 1990, scientists from across the world collaborated in the Human Genome Project to do just that and in 2003, they announced that there are about 24,000 genes in each human. This is less than the 100,000 genes scientists had anticipated and, surprisingly, not much more than a chimpanzee or mouse.

There are several forms of genetic disorders and one type is due to a mutation in a single gene, i.e. monogenic disorders. Familiar examples include cystic fibrosis, sickle cell disease and polycystic kidney disease. Have we made any therapeutic breakthroughs since deciphering the human genome and what are the challenges involved in gene therapy?

Gene therapy in medicine

In March 2017, the Necker’s Children’s Hospital in Paris announced the ‘cure’ of a 15 year-old boy suffering from sickle cell disease. The disorder is due to a faulty gene which codes for the production of a sub-unit of haemoglobin, beta globin, leading them to clump together inside red blood cells and thus distorting the cells into abnormal sickle shape. Doctors initially removed stem cells from the boy’s bone marrow and then used a viral vector to insert a copy of the ‘correct’ gene into the stem cells. (For the technically minded: bone marrow-enriched CD34+ cells were transduced with LentiGlobin BB305 containing self-inactivating lentiviral vector encoding the human HBB variant ẞA-T87Q.)

The modified stem cells were then transplanted into the patient and after three months he was producing large quantities of normal haemoglobins, and after six months his doctors concluded that his red blood cells were behaving normally. Fifteen months after treatment, previous medications were stopped and he was described by his doctors as living a ‘pretty normal life’. Importantly, no adverse events were considered  to be related to the BB305-transduced cells. Seven other  patients have undergone similar treatments and are also showing promising results.

Big pharma has also entered the field with gusto. In August 2017, Novartis’ Kymriah (tisagenlecleucel), developed in collaboration with the University of Pennsylvania, became the first gene therapy to be approved by the FDA. It is licensed to treat a form of B-cell acute lymphoblastic leukaemia in patients who have not responded to previous therapies. A product as well as a process, Kymriah utilises a technology known as CAR-T (chimeric antigen receptor-T cell), which has been described as a ‘cure’ for some cancers. The process involves extracting a patient’s own immune T-cells, transducing them with a gene that allows the T-cells to form surface receptors which enable them to identify and destroy hidden cancer cells containing specific surface antigens (CD19). Sounds easy but the logistics are highly complex. Following extraction, a patient’s T-cells are cryogenically frozen and shipped to Novartis’ New Jersey manufacturing centre, the cells are then genetically engineered to carry the ‘therapeutic gene’. (UK based Oxford BioMedica is the sole manufacturer of the lentiviral vector that encodes Kymriah.) In a clinical trial of 63 patients with Kymriah, the overall remission rate after three months was 83 percent. In January 2018, the EMA granted Kymriah  an accelerated assessment for an  EU licence.

Moving swiftly, in October 2017 the FDA approved a second gene therapy, Yescarta (axicabtagene ciloleucel) another CAR-T, for certain types of large B-cell lymphoma after failure with current treatments. In a clinical trial of more than 100 patients with Yescarta, the complete remission rate was 51 percent. It was initially developed by the US National Cancer Institute before being licensed to Kite Pharma. Weeks before  the approval of Yescarta, Kite was acquired by Gilead. The ‘product’ will be manufactured in California and is also  awaiting an EU licence.

Both CAR-T treatments come with the potential to cause severe side effects like ‘cytokine storms’ (when the immune system goes into hyperdrive) and neurological toxicities, both of which are potentially fatal. They can also cause serious infections, as the CD19 antigens targeted by CAR-T are found on normal immune B-cells as well. There were three deaths related to Yescarta in the clinical trials while none died in the
Kymriah programme.

The principle of using a patient’s own stem cells and a lentiviral vector is also employed by Orchard Therapeutics. Unlike the above blood cancer indications, Orchard’s work lies in non-cancer orphan diseases like primary immune deficiencies and inherited metabolic diseases. In a reversal of Big Pharma acquiring ‘rising stars’ with cutting-edge products, in April 2018 GSK relinquished its rare diseases portfolio to Orchard, transferring its approved and investigational gene therapies while maintaining a minority equity stake. The transfer included Strimvelis, approved by the EMA in May 2016 for children with adenosine deaminase severe combined immunodeficiency (bubble baby syndrome), plus three ongoing clinical programmes including one for beta-thalassaemia.

What are the downsides?

The one-off acquisition costs for the therapies are pretty astronomical: Yescarta $373,000, Kymriah $470,000 and Strimvelis $648,000. It is estimated that payers may have to factor an additional 50-150 percent overheads to cover for consultations, hospitalisations and logistic expenditures. Furthermore, the FDA has mandated costly risk management programmes for both CAR-T products due to the aforementioned severe side effects. Interestingly, Novartis is offering a value-based pricing whereby US insurers will only need to pay if patients go into remission within three months, while Gilead will offer financial help for patients but no value-based scheme.

Another consideration is that the treatments can only be processed in the approved manufacturing facilities: for Kymriah  and Yescarta, one would assume that ex-US patients’ stem cells would need to be flown to New Jersey and California respectively. There is the added challenge of standardising the quality of the ‘end products’ using stem cells from individual patients.
Slow uptake is to be expected as existing healthcare ecosystems are not equipped to handle this type of quantum-leap technology. It took an entire year post-authorisation before the first patient was treated with Strimvelis at its Milan facility. Likewise, two months after approval, only five patients were treated with Yescarta despite a waiting list of at least 200 in the US.

A survey in Dec 2017 of 200 American oncologists by Cardinal Health found that 51 percent of respondents thought that CAR-T is a ‘game changer’ in oncology; albeit with concerns about logistical complexity (59 percent), cost of therapy (44 percent) and high toxicity (35 percent).

Nonetheless, the chief executive of NHS England indicated that CAR-T could be available on the NHS this year, with the caveat that manufacturers “need to set fair and affordable prices so that they are both affordable and sustainable in the long term’. A surprising stance given that both CAR-T treatments are still undergoing NICE consultation. However, advocates pointed out that a NICE ‘mock technology appraisal’ into CAR-T published in February 2017, indicate that the therapies could be worth as much as £500,000.

Let’s hope the new gene therapies do not go the way of Glybera (alipogene tiparvovec for inherited disorder lipoprotein lipase deficiency from Amsterdam-based uniQure). It became the first EMA licensed gene therapy in Nov 2012 and the EU’s most costly ‘drug’ at €1 million. However, it was withdrawn in April 2017 due to onerous post-marketing safety obligations, low uptake and crucially, its failure to secure a US licence.

Dr Stephen Huang is a pharmaceutical medicine consultant and James Huang is a policy researcher, both at SCP Medical